EP1236725B1 - Neue 1,8-naphtyridin-2(1h)-on-derivate - Google Patents

Neue 1,8-naphtyridin-2(1h)-on-derivate Download PDF

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EP1236725B1
EP1236725B1 EP00979982A EP00979982A EP1236725B1 EP 1236725 B1 EP1236725 B1 EP 1236725B1 EP 00979982 A EP00979982 A EP 00979982A EP 00979982 A EP00979982 A EP 00979982A EP 1236725 B1 EP1236725 B1 EP 1236725B1
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diseases
app
pyridin
pharmaceutically acceptable
naphthyridin
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EP1236725A4 (de
EP1236725A1 (de
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Tomoji Aotsuka
Kentarou Kumazawa
Nagatoshi Wagatsuma
Kouki Ishitani
Takashi Nose
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Aska Pharmaceutical Co Ltd
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Grelan Pharmaceutical Co Ltd
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Definitions

  • the present invention relates to novel 1,8-naphthyridin-2(1H)-one derivatives that selectively inhibit phosphodiesterase (hereinafter, referred to as "PDE") IV, or pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising the same.
  • PDE phosphodiesterase
  • the present invention also relates to prophylactic and/or therapeutic drugs (including antiasthmatics) for diseases associated with PDE IV actions, which comprise each an effective amount of at least one member selected from the 1,8-naphthyridin-2(1H)-one derivatives and salts thereof.
  • PDEs are enzymes which hydrolyze intracellular cyclic AMP (cAMP) and intracellular cyclic GMP (cGMP) and widely distributed in vivo in various tissues and organs.
  • cAMP intracellular cyclic AMP
  • cGMP intracellular cyclic GMP
  • PDE I to VII intracellular cyclic GMP
  • PDE IV is known to be an enzyme which is predominantly present in airway smooth muscle cells and a wide variety of inflammatory cells, i.e., neutrophils, eosinophils, lymphocytes, etc. and selectively breaks down cAMP.
  • cAMP levels in airway smooth muscle cells leads to relaxation of the airway smooth muscles.
  • An increase of cAMP levels in inflammatory cells has also been known to suppress an activation of inflammatory cells, including, for example, a release of cytotoxic proteins from eosinophils, etc.
  • theophylline which is a xanthine derivative, rolipram, which is a catechol derivative, etc. are inhibitors of PDE IV.
  • Theophylline inhibits PDE in various tissues due to its non-selectivity for individual isozymes, thereby exerting not only a bronchodilator activity to be targeted but also extra actions on heart, CNS, etc.
  • rolipram is observed to be selective for PDE IV, it is easily transferred into the CNS due to its property of being absorbed. Therefore, rolipram has a drawback that it induces adverse central side-actions such as an emetic action.
  • PDE IV-inhibitory compounds having a naphthyridine ring have been proposed in WO 94/12499, A1; JP, A, 7-10875 (1995); WO 96/6843, A1; JP, A, 11-106385 (1999); etc.
  • JP, A, 63-159382 (1988) discloses 1-substituted naphthyridine derivatives having, on the position 3, a substituent selected from alkyl, cycloalkyl, phenyl, phenylalkyl, etc., which are deemed useful in the treatment of allergy, inflammation, and the like, though no mention is made of PDE IV-inhibiting actions.
  • the present inventors have conducted an extensive research on various compounds in order to solve the above problems. As a result, the present inventors have succeeded in producing novel 1,8-naphthyridin-2(1H)-one derivatives which exert selective inhibition against PDE IV. Further, the present inventors have found that the compounds of the present invention are not only unexpectedly advantageous over the conventional PDE IV inhibitors but also qualified as potent inhibitors of PDE IV from aspects of pharmacological action and safety, and succeeded in accomplishing this invention.
  • the present invention encompasses 1,8-naphthyridin-2(1H)-one derivative compounds having a heteroaryl group, or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, via 1 to 8 methylene chains on the 3 position of the 1,8-naphthyridin-2(1H)-one nucleus and pharmaceutical compositions comprising an effective amount of the said compound.
  • the compounds of the invention are naphthyridine derivatives having a heteroaryl group, or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, via 1 to 8 methylene chains on the 3 position of the 1,8-naphthyridine nucleus, it is apparent that the inventive compounds are structurally different from 1-substituted naphthyridine derivatives disclosed in JP, A, 63-159382 (1988). As described hereinbelow, the compounds of the invention are also distinct from the compounds disclosed in JP, A, 63-159382 (1988) because their PDE IV-inhibiting activity is significantly superior to that of the prior art compounds.
  • the present invention provides the following:
  • the present invention provides compounds, or salts thereof, having an unsubstituted or optionally substituted 5 to 6 membered heteroaryl group or a fused ring in which any of the heteroaryl groups is contained (for example, a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring), via a chain comprised of 1 to 8 members of methylene, on the position 3 of a 1,8-naphthyridin-2(1H)-one ring, which possess advantageous biological properties, and pharmaceutical compositions comprising at least one member selected from the aforementioned compounds and pharmaceutically acceptable salts thereof.
  • the compounds or salts thereof are utilizable for their selective PDE IV-inhibiting actions.
  • the present invention also provides drugs for preventing and/or treating at least one member selected from diseases, disorders, and abnormal conditions related to an activity of PDE IV.
  • any of 1,8-naphthyridin-2(1H)-one rings known in the art prior to the present case may be adoptable without any limitations wherein such 1,8-naphthyridin-2(1H)-one rings may have any of all substituents known to be placed on any of positions other than the position 3 of the 1,8-naphthyridin-2(1H)-one ring.
  • a preferred embodiment of the present invention is as follows:
  • a 5 or 6 membered heteroaryl group or a fused benzene ring in which any of the above-defined heteroaryl groups is fused to a benzene ring refers to a 5 or 6 membered heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of N, S, and O; or a fused benzene ring in which any of the above-defined heteroaryl groups is fused to a benzene ring.
  • heteroaryl groups and fused benzene rings include pyrrolyl, pyridyl, 1-oxypyridyl, thienyl, furyl, imidazolyl, thiazolyl, oxazolyl, indolyl, quinolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, etc.
  • preferred groups include pyridyl, 1-oxypyridyl, thienyl, furyl, thiazolyl, and benzothiazolyl.
  • pyridyl and 1-oxypyridyl are preferable. Examples of the pyridyl are 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.
  • the heteroaryl group and the fused benzene ring may be unsubstituted or optionally substituted with one or more substituents.
  • the substituents include lower alkyl, lower alkoxy, hydroxyl, halogen, nitro, halogen-substituted lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, a residue derived from carboxylic acids and derivatives thereof, such as alkoxycarbonyl, and an amino nitrogen-containing radical such as di-lower alkylamino.
  • lower alkyl refers to alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and isopropyl.
  • halogen refers to fluorine, chlorine, bromine, and the like.
  • lower alkylthio refers to alkylthio containing 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, and isopropylthio.
  • lower alkylsulfinyl refers to alkylsulfinyl containing 1 to 4 carbon atoms, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, and isopropylsulfinyl.
  • lower alkylsulfonyl refers to alkylsulfonyl containing 1 to 4 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl.
  • lower alkoxy refers to alkoxy containing 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, and isopropoxy.
  • Preferred compounds according to the present invention have the structural formula (1). Still more preferred compounds according to the present invention have the structural formula (1) wherein A is pyridyl or 1-oxypyridyl; and m is selected from 1 to 5.
  • Representative examples of compounds of the invention include the following:
  • the compound(s) of the present invention may include salts thereof, hydrates and solvates thereof, a variety of prodrug forms derived from functional groups existing in compound molecules.
  • the prodrugs of the compounds according to the present invention include those compounds which can be transformed in vivo , for example, by metabolic processes, including hydrolysis, oxidation, reduction, trans-esterification, and the like, to yield the parent compounds of the formula (1), etc.
  • Representatives of such prodrugs are ester-, ether-, amide-, alcohol-, and amine-derivatives thereof.
  • Preferred compounds according to the present invention are potently active in the inhibition of IV-type phosphodiesterases.
  • Some of the compounds of formula (1) may exist in more than one tautomeric form. This invention extends to all tautomeric forms.
  • the compounds of the instant invention may also contain one or plural asymmetric carbon atoms and thus give rise to optical isomers such as (R)- and (S)-isomers, racemates, diastereoisomers, etc.
  • the present invention includes all such possible isomers, and their racemic and resolved, enantiomerically pure forms, as well as all mixtures thereof.
  • the compounds of the invention may be isolated in the form of hydrates, solvates with, for example, ethanol and the like, and a variety of crystalline substances.
  • the present invention also encompasses pharmaceutically acceptable salts of the naphthyridine derivative having the formula (1).
  • Such salts include those formed from any of medically or pharmaceutically utilizable non-toxic or low toxic inorganic or organic acids. Examples of the salts are hydrochloride, hydrobromate, sulfate, acetate, propionate, citrate, succinate, tartrate, methanesulfonate, p-toluenesulfonate, etc.
  • the compounds of the present invention can be prepared by one of various routes.
  • the compounds of the formula (1) can be prepared by one of the following schemes or modifications thereof:
  • the compounds of the formula (1) wherein A, B, R 1 , R 2 and m, all have the meanings given above can be prepared by condensing a compound of the formula (2) wherein B, R 1 and R 2 , all have the meanings given above with a compound of the formula (3) wherein R 3 is lower alkyl, and m and A, both have the meanings given above in the presence of a base.
  • the lower alkyl for R 3 has the same meaning as in the above-defined compounds of the formula (1) and refers to alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and isopropyl.
  • Bases used in this condensation may include alkali metal amides, alkali metal hydrides, alkyl lithium, aryl lithium, and the like.
  • Examples of the base are lithium diisopropylamide (LDA), sodium bistrimethylsilylamide, potassium hydride, methyl lithium, phenyl lithium, etc.
  • LDA lithium diisopropylamide
  • the reaction can be conducted in the presence of or in the absence of a solvent. When the reaction is conducted in solvents, it is often convenient to use conventional solvents which are free from any adverse action on the reaction.
  • Preferred examples of such solvents are tetrahydrofuran (THF), diethyl ether, methylene chloride, etc.
  • the reaction temperature range is about -80 to 100°C and preferably about - 80°C to room temperature.
  • the compounds of the formula (2) can be prepared by one of known methods (e.g., JP, A, 62-158281 (1987); JP, A, 62-228076 (1987); etc.) or modifications thereof.
  • the compounds of the formula (3) can be prepared, for example, by one of the synthetic routes described herein.
  • the disclosures given below illustrate the preparation of compounds of the formula (3) wherein A is pyridyl.
  • the compounds of the formula (3) wherein A is pyridyl and m is 1, 2 or 3 can be prepared according to one of Schemes (IIa), (IIb) and (IIc) outlined as follows:
  • a pyridylacrylic acid ester (6) can be prepared by condensing a pyridine aldehyde (4) with a diethylphosphonoacetic acid lower alkyl ester of the formula (5) wherein R 3 has the same meaning as defined above in the presence of a base such as sodium hydride.
  • a compound of the formula (3) wherein A is pyridyl and m is 1 (Compound (3a)) can be prepared by reduction of the compound (6).
  • the reduction of the compound (6) can be effected generally by hydrogenation in the presence of a suitable catalyst such as palladium on carbon.
  • a compound (9) can be prepared by addition of ethyl malonate (8) to vinylpyridine (7) in the presence of a suitable base such as sodium methoxide or sodium ethoxide. Next, the compound (9) can be hydrolyzed under acidic conditions (for example, with conc. hydrochloric acid) and then decarboxylated to give a carboxylic acid derivative (10).
  • a compound of the formula (3) wherein A is pyridyl and m is 2 (Compound (3b) can be prepared by esterification of the carboxylic acid derivative (10) with a lower alkyl alcohol of the formula: R 3 OH wherein R 3 has the same meaning as defined above. It should be noted that the aforementioned compounds (3b) may be prepared by processes entirely different from the Scheme (IIb), i.e., they can be prepared according to the procedure of Synthetic Example 7 given below.
  • a compound (12) can be prepared by condensing a pyridine aldehyde (4) with a diethylphosphonocrotonic acid lower alkyl ester of the formula (11) wherein R 3 has the same meaning as defined above in the presence of a base such as LDA.
  • a compound of the formula (3) wherein A is pyridyl and m is 3 (Compound (3c)) can be prepared by reduction (for example, catalytic reduction) of the compound (12).
  • the catalytic reduction may be effected by techniques similar to the reduction in the Scheme (IIa).
  • a bromoalkyl carboxylic acid (13) is reacted with triphenylphosphine to produce a phosphonium salt (14) which is then treated with a base prepared from sodium hydride and dimethylsulfoxide (DMSO) to give a phosphorane.
  • DMSO dimethylsulfoxide
  • the resultant phosphorane is reacted with a pyridine aldehyde (4) followed by treatment with chloroacetonitrile.
  • the resulting cyanomethyl ester derivative (15) is subjected to a trans-esterification using a lower alkyl alcohol of the formula: R 3 OH wherein R 3 has the same meaning as defined above in the presence of a catalytic amount of triethylamine to produce a lower alkyl ester derivative (16) which is then reduced to give a compound of the formula (3) wherein A is pyridyl and m is selected from 4 to 8 (Compound (3d)).
  • the reduction of the lower alkyl ester derivative (16) may be conducted by techniques similar to the catalytic reduction in the Scheme (IIa).
  • the compounds of the present invention so prepared may be isolated or purified as free forms per se or in the form of salts after being subjected to conventional salt-forming treatments.
  • the isolation and purification can be effected by adaptations of ordinary chemical operations including, for example, extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatographic techniques, etc.
  • Various isomers can be separated by conventional methods utilizing a difference of physico-chemical properties among such isomers.
  • stereochemically pure isomers can be obtained from racemic mixtures by an ordinary racemic resolution (for example, by first converting said racemic mixtures with usual optically-active acids (including tartaric acid, etc.) to diastereomer salts followed by optical resolution, etc.).
  • Diastereomers can be separated by ordinary methods such as selective crystallization or chromatographic techniques. Pure optically-active isomeric forms of the compounds of the present invention may also be obtained from the pure optically-active isomeric forms of the appropriate starting materials and intermediates
  • the compounds of the present invention are potent inhibitors of PDE IV.
  • the compounds of the present invention are thus of use in the prophylaxis and treatment of diseases and abnormal states related to PDE IV actions.
  • the compounds of the present invention are effective as prophylactic or therapeutic agents for diseases and conditions associated with an abnormal enzymatic or catalytic activity of PDE IV.
  • the compounds of the present invention are of use in medicine, especially in the prophylaxis and treatment of:
  • the compounds of the present invention act as prophylactic and/or therapeutic drugs for:
  • the compounds of the present invention act as drugs for preventing and/or treating at least one disease or abnormal state selected from respiratory diseases (including, for example, bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease; acute respiratory distress syndrome (ARDS); etc.).
  • respiratory diseases including, for example, bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease; acute respiratory distress syndrome (ARDS); etc.
  • the compounds of the present invention are most preferably effective as prophylactic and/or therapeutic drugs for bronchial asthma.
  • the compounds of the present invention are particularly useful in treating or preventing diseases or abnormal states because they are significantly less emetic than the prior art PDE IV inhibitors.
  • the compounds of the present invention are effective in treating or preventing diseases or abnormal states wherein they are required to be administered systemically or locally.
  • the present invention encompasses pharmaceutical compositions comprising an effective amount of at least one member selected from the above-defined compounds (1) and pharmaceutically acceptable salts thereof, and not only inhibitors of PDE IV but also pharmaceutical drugs for preventing or treating at least one member selected from diseases and abnormal conditions related to an activity of PDE IV, more preferably anti-asthmatic agents.
  • the compounds of the present invention inhibit selectively PDE IV in these cells, thereby exerting a bronchodilator action via relaxing airway smooth muscles, together with an anti-inflammatory action through suppressing inflammatory cell activation.
  • the compounds of the present invention are widely effective in ameliorating a variety of undesirable responses and symptoms raised with regard to asthma.
  • the immediate asthmatic response that begins immediately after inhalation of antigens is a typical airway smooth muscle constrictive reaction induced by chemical mediators (including histamine, leukotrienes, etc.) which are released from mast cells as a result of antigen-antibody interactions. Later the delayed asthmatic response is observed, which occurs within 4 to 24 hours after the inhalation of antigens. For its pathological states, an infiltration of inflammatory cells into lung tissues, airway mucosa edema, etc. are observed. Thereafter, the hypersensitive airway response is further elicited, which occurs within 1 to 14 days after the inhalation of antigens and is a state wherein the airway reactivity is increased. In such a stage, even quite mild stimuli lead to constriction of the airway and occurrence of serious airway obstruction.
  • chemical mediators including histamine, leukotrienes, etc.
  • the compounds of the present invention can exert an excellent inhibitory and/or ameliorating activity on such responses and symptoms at each stage, relying on their bronchodilator and anti-inflammatory actions based on the inhibition of PDE IV.
  • the PDE-inhibiting action exerted by the compounds of present invention is highly selective against PDE IV but less selective for other isoenzymes located in certain tissues such as CNS and heart, it may be possible to avoid side-effects (for example, spasm, tachycardia, palpitation, etc.) caused by the inhibition of these isoenzymes when the present invention is applied.
  • Diseases and abnormal states to be targeted by the therapy using the compounds of the present invention include the aforementioned diseases and abnormal conditions, preferably diseases and abnormal conditions accompanied with respiratory dysfunctions and inflammation at the area of bronchus and airway.
  • diseases and abnormal conditions include bronchial asthma, chronic bronchial asthma, acute bronchitis, chronic bronchitis, asthmatic bronchitis, pulmonary emphysema, and other bronchus and airway inflammatory states, etc.
  • chronic bronchitis and pulmonary emphysema may also be generically termed chronic obstructive pulmonary disease.
  • the compounds of the present invention can be used independently without any additives, but preferably in admixture with any of pharmaceutically acceptable additives.
  • the compounds of the present invention may be orally, parenterally (including by injection), topically (including by inhalation) administered as pharmaceutical compositions or formulations.
  • One or more components selected from known pharmaceutical additives (hereinafter also referred to "pharmaceutical ingredient(s)") can be employed in the aforementioned pharmaceutical compositions or formulations for any of administration routes.
  • pharmaceutical additives may be suitably selected, according to administration routes and applications of pharmaceutically formulated forms, from components as disclosed in, for example,
  • the aforementioned additives are any pharmaceutical ingredients as long as they are suitable for oral drugs and the intended purposes according to the present invention.
  • the pharmaceutical additive is selected from conventional pharmaceutical ingredients such as vehicles, binders, disintegrants, lubricants and coating agents.
  • the oral formulations of the present invention include tablets, capsules, granules, fine granules, powders, syrups, etc.
  • the oral drug includes controlled-release system preparations wherein the in vivo release of the compound of the present invention which is contained as the active ingredient is controlled using any of known pharmaceutical ingredients (for example, immediate-release preparations, sustained-release preparations, etc.).
  • the aforementioned oral drug may include enteric preparations.
  • the oral drugs are prepared in the form of such enteric preparations.
  • enteric preparations include coated or matrix formulations using any of enteric coating agents such as cellulose phthalate, hydroxypropyl methylcellulose phthalate, and methyl methacrylate-methacrylic acid copolymers, among the coating agents given below, and capsule formulations wherein any of the enteric coating agents is contained as an ingredient for their coat.
  • Embodiments of pharmaceutical ingredients as used for the aforementioned oral drugs are listed below but not limited to:
  • the additives include pharmaceutical ingredients suitable for aqueous or non-aqueous injections.
  • the additive is selected from conventional pharmaceutical ingredients such solubilizers, solution adjuvants, suspending agents, buffers (pH regulators), stabilizers and preservatives.
  • it may be selected from conventional ingredients suitable for preparing powders for injection, which are used in solution or suspension when administered.
  • solubilizers for injections include water for injection, physiological saline, Ringer's solution, vegetable oil (for example, olive oil, sesame oil, soybean oil), ethanol, propylene glycol, polyethylene glycol, glycerin, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.
  • solution adjuvants include polyethoxylated hydrogenated castor oil, ethylene diamine, benzyl alcohol, Polysorbate 80, carboxymethylcellulose sodium, sodium hydroxide, sodium citrate, sodium acetate, potassium dihydrogen phosphate, sodium hydrogen sulfite, ascorbic acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, etc.
  • constituents for powdered injections include glucose, sorbitol, etc.
  • the aforementioned additives as used herein include any of pharmaceutical ingredients known in the art, such as solution adjuvants, stabilizers, buffers, suspending agents, emulsifying agents, and preservatives.
  • Embodiments of inhalants include aerosols. Aerosol-producing techniques are any of types including a spraying type wherein active drug ingredients are packed together with propellants such as fluorocarbon alternatives into a sealed container and sprayed, and a nebulizer or atomizer type using a pressured gas, such as carbon dioxide and nitrogen, filled in a container different from that for active drug ingredients.
  • representatives of pharmaceutical ingredients such as propellants, solution adjuvants, stabilizers, buffers, suspending agents, emulsifying agents, and preservatives, include chlorine-free fluorinated hydrocarbons [e.g., 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227), etc.], alcohol, propylene glycol, polyethylene glycol, Polysorbate 80, glycerin, egg yolk lecithin, soybean lecithin, ⁇ -tocopherol, ascorbic acid, benzalkonium chloride, chlorobutanol, etc.
  • chlorine-free fluorinated hydrocarbons e.g., 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227), etc.
  • alcohol propylene glycol
  • polyethylene glycol polyethylene glycol
  • the pharmaceutical ingredients as used may include water for injection, purified water, etc.
  • the inhalants may also be prepared in the form of not only sprays wherein any of the above-defined propellants is used, nebulizers or atomizers, but also powders.
  • powder inhalants can be in any of forms similar to available powder inhalants in the art (e.g., INTAL (registered trademark) capsule and metered-dose inhaler: SPINHALER (registered trademark); for administration of sodium chromoglicate).
  • the compounds of the present invention may be administered topically in the form of ointments, transdermic patches, solutions for external use, eyedrops, nose drops or suppositories.
  • topical pharmaceutical preparations may suitably contain pharmaceutical ingredients as disclosed in the aforementioned "Iyakuhin Tenkabutsu Handbook (Handbook of PHARMACEUTICAL EXCIPIENTS)", “Iyakuhin Tenkabutsu Jiten (Pharmaceutical Excipient Dictionary)", etc.
  • Desired oral drugs, injections or drugs for topical applications comprising the compound of the present invention in admixture with the aforementioned ingredient can be prepared according to manufacturing methods known per se , for example, those described in The 13th Pharmacopoeia of Japan (JPXIII) or appropriately modified ones.
  • the pharmaceutical compositions (drugs) of the present invention are administered to mammals, particularly including human.
  • the doses of these compounds or salts thereof are usually about 0.1 to 1,000 mg (per day), preferably about 0.1 to 500 mg (per day) for oral administration; usually about 0.01 to 200 mg (per day), preferably about 0.05 to 100 mg (per day) for injection; and usually about 0.01 to 200 mg (per day), preferably about 0.05 to 100 mg (per day) for topical applications.
  • Type I, II, III and IV PDEs as used herein were separated from porcine hearts by using an anion exchange chromatography.
  • Type V PDE was also separated from porcine aortae with an anion exchange chromatography and used herein.
  • Each PDE isozyme was admixed with ethylene glycol (EG) to adjust the final EG concentration to 30%, then stored at -20 °C and diluted when used.
  • EG ethylene glycol
  • the enzymatic activity for PDE I and V was measured using cGMP as a substrate while that for PDE II, III and IV was measured using cAMP.
  • [ 3 H]-cAMP (962 GBq/mmol; Amersham, 25 ⁇ l (100,000 cpm)) or [ 3 H]-cGMP (962 GBq/mmol; Amersham, 25 ⁇ l (100,000 cpm)) was added together with each PDE isozyme (25 ⁇ l) to an incubation buffer solution with the composition given below to adjust the total volume to 250 ⁇ l.
  • Each test compound was dissolved in DMSO to adjust the final concentration to 1% (2,5 ⁇ l/tube).
  • Tris-HCl 50mM
  • magnesium chloride 6mM
  • dithiothreitol 2.5mM
  • 5-nucleotidase 4 ⁇ g/ml
  • bovine serum albumin 0.23mg/ml
  • cAMP 1 ⁇ M
  • cGMP 1 ⁇ M
  • a mixture of the aforementioned test compound solution and the buffer solution was incubated at 30°C for 20 minutes.
  • the reaction was quenched by admixing with 1 ml of anion exchange resin slurry (AG1-X8, 200-400 meshes, chloride form; Bio-Rad) to absorb unreacted substrates.
  • anion exchange resin slurry AG1-X8, 200-400 meshes, chloride form; Bio-Rad
  • % inhibition was calculated for test compounds, and IC 50 (the concentration of each test compound required for 50% inhibition) was obtained by Probit method. The results are shown in Table 1.
  • Example No. 14 >100 >100 >100 2.2 >100
  • Example No. 23 >100 >100 >100 1.2 >100
  • mice Male Hartley outbred guinea pigs were sensitized by administering intraperitoneally physiological saline (0.5 ml) containing ovalbumin (1 mg, antigen) and 5 x 10 9 inactivated Bordetella pertussis dead cells (adjuvant).
  • the guinea pigs (3 animals per group) actively sensitized in the above step (1) were employed to measure for their airway pressure according to Konzett-Rossler method (Arch. Exp. Path. Pharmakol., 195 , 71 (1940)).
  • guinea pigs fasted overnight, and were on the next day anesthetized with a pentobarbital solution (60 mg/1.2 ml/kg, dissolved in physiological saline, intraperitoneal administration).
  • a pentobarbital solution 60 mg/1.2 ml/kg, dissolved in physiological saline, intraperitoneal administration.
  • a 4-port cannula was incised followed by insertion with one port of a 4-port cannula.
  • 2 ports were connected to an artificial respirator (Model 683, Harvard). The animals were ventilated with 10 ml/kg of air per ventilation at a rate of 60 beats/min via the artificial respirator from the cannula.
  • One port remainder was connected to a respiratory amplifier (AR-601G, Nihon Kohden, Japan) via an airflow resistance tube (TV-241T, Nihon Kohden, Japan) and a differential pressure transducer (TP-602T, Nihon Kohden, Japan) connected with a control box (RY-111S, Nihon Kohden, Japan).
  • a respiratory amplifier AR-601G, Nihon Kohden, Japan
  • an airflow resistance tube TV-241T, Nihon Kohden, Japan
  • TP-602T differential pressure transducer
  • RY-111S Nihon Kohden, Japan
  • test compound was suspended in 0.5% CMC-Na solution and administered orally with an oral sound at a dose of 3 mg/2 ml/kg 60 minutes prior to the antigen-challenge.
  • Control groups received only 0.5% CMC-Na solution in an equivalent amount.
  • the pentobarbital-anesthetization and tracheal incision were conducted 30 minutes prior to the antigen-challenge.
  • the compounds of the present invention i.e., Example No. 5 Compound and Example No. 8 Compound, exert 86% and 88% reductions, respectively, of increase in airway resistance.
  • Compounds A and D are merely 68% and 70%, respectively, for the reduction of increase in airway resistance.
  • Rolipram's percent reduction of increase in airway resistance is only 65%. Accordingly, it has been ascertained that the compounds of the present invention reverse an increase in airway resistance more excellently than the compounds as disclosed in JP, A, 63-159382 (1988).
  • Each Compound (Example Nos. 8 and 10) was administered orally to CD (SD) rats (5 animals per group) as a test compound once a day for 4 successive weeks in a forced manner.
  • the rats were observed for the time course of their general health conditions and measured for their body weight.
  • organs were weighed, and main organs were further examined pathohistologically.
  • Each test compound was suspended in 0.5% CMC-Na solution and given orally to the animal at a dose of 1 mg/5 ml/kg or 5 mg/5 ml/kg in a forced manner.
  • mice Ten percent proteose peptone (2 ml/animal) was administered intraperitoneally to male C3H/HeN mice (6- to 8-week-old) for inducing peritoneal macrophages.
  • mice Four days after the proteose peptone administration, mice were sacrificed by the dislocation of cervical vertebrate, bled with cutting of their carotid artery, douched intraperitoneally with ice-cooled RPMI 1640 (6ml), massaged, and lavage fluids wherein peritoneal exudate cells suspended were harvested. The resulting cell suspension was centrifuged at 200 x g, and obtained cell pellets were treated with a Tris-ammonium buffer for 1 minute to hemolyze erythrocyte contaminants.
  • the resulting cells were washed twice with 10% FBS/RPMI 1640, resuspended, and seeded on 96-well plates (Sumitomo Bakelite, Japan) at 5 x 10 5 cells/0.2 ml/well. After pre-incubation for 2 hours in an atmosphere of 5% CO 2 /95% air, each well was rinsed 3 times with PBS(-) to remove non-adhesive cells.
  • test compound was dissolved in DMSO, and then in 10% FBS/RPMI 1640 to make the final DMSO concentration 0.1%.
  • the resultant test compound solution was used herein.
  • an aliquot of macrophages prepared in the above (1) was admixed with LPS ( E. coli serotype 0127: B8; Sigma) to adjust the final LPS concentration to 0.1 ⁇ g/ml.
  • LPS E. coli serotype 0127: B8; Sigma
  • culture supernatants were harvested and stored at -80°C. Amounts of TNF ⁇ in the culture supernatants were measured with a mouse TNF ⁇ ELISA kit (Quantikine/trade name; R & D Systems) according to manuals attached to the kit.
  • Example No. 8 Compound When the above assay was applied to Example No. 8 Compound and rolipram, their excellent inhibitory activity on the production of TNF- ⁇ were observed.
  • the IC 50 value for Example No. 8 Compound is 0.34 ⁇ g/ml (about 0.88 ⁇ M) and that for rolipram 0.37 ⁇ g/ml (about 1.3 ⁇ M).
  • the resultant mixture was diluted with ethyl acetate, washed successively with dilute hydrochloric acid (1N, twice), saturated aqueous sodium chloride, saturated aqueous carbonic acid (twice) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated.
  • Ethyl 3-(pyridin-2-yl)propionate (0.717g, 2.0 eq., prepared in Synthetic Example 4) was dissolved in dry THF. To the solution was added LDA (2ml of 2M solution, 2.0 eq.) at -78°C or below in a methanol-dry ice bath under nitrogen atmosphere while stirring and the mixture was stirred for 1 hour.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 3-(pyridin-3-yl)-propionate (1.2 eq., prepared in Synthetic Example 5) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-(pyridin-3-ylmethyl)-1,8-naphthyridin-2(1H)-one, mp 226 to 227°C/DMF.
  • 2-(3-nitrophenylamino)nicotinaldehyde 1.0 eq.
  • ethyl 3-(pyridin-3-yl)-propionate 1.2 eq., prepared in Synthetic Example 5
  • LDA 1.5 eq.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-cyanophenylamino)nicotinaldehyde (1.0 eq., prepared according to the procedure of Example 3 in JP, A, 62-228076 (1987)), ethyl 3-(pyridin-4-yl)propionate (1.1 eq., prepared in Synthetic Example 6) and LDA (1.5 eq.) to obtain 1-(3-cyanophenyl)-3-(pyridin-4-ylmethyl)-1,8-naphthyridin-2(1H)-one, mp 229 to 230°C/DMF.
  • 2-(3-cyanophenylamino)nicotinaldehyde 1.0 eq., prepared according to the procedure of Example 3 in JP, A, 62-228076 (1987)
  • ethyl 3-(pyridin-4-yl)propionate 1.1 eq., prepared in Synthetic Example 6
  • LDA 1.5 eq.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 3-(pyridin-4-yl)-propionate (1.1 eq.) and LDA (1.5 eq.) to obtain a product which was subjected to recrystallization from ethyl acetatemethanol to give 1-(3-nitrophenyl)-3-(pyridin-4-ylmethyl)-1,8-naphthyridin-2(1H)-one as a pale brown powder, mp 230°C/EtOAc-MeOH (decomp.).
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-3-yl)-butanoate (1.3 eq., prepared in Synthetic Example 7) and LDA (1.3 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-3-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 221 to 223°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(pyridin-4-yl)-butanoate (1.1 eq., prepared in Synthetic Example 8) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 213 to 214°C/DMF-EtOH.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-3-yl)-pentanoate (1.1 eq., prepared in Synthetic Example 9) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 172 to 173°C/DMF-EtOH.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-4-yl)-pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 209 to 210°C/DMF-EtOH.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-chlorophenylamino)nicotinaldehyde (1.0 eq., prepared according to the procedure of Example 3 in JP, A, 62-228076 (1987)), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 1-(3-chlorophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 148 to 149°C/AcOEt.
  • 2-(3-chlorophenylamino)nicotinaldehyde 1.0 eq., prepared according to the procedure of Example 3 in JP, A, 62-228076 (1987)
  • ethyl 5-(pyridin-4-yl)pentanoate 1.5 eq.
  • LDA 1.5 eq.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-methylthiophenylamino)nicotinaldehyde (1.0 eq., prepared according to the procedure of Example 3 in JP, A, 62-228076 (1987)), ethyl 5-(pyridin-4-yl)pentanoate (2.0 eq.) and LDA (2.0 eq.) to obtain 1-(3-methylthiophenyl)-3-[3-(pyridin-4-yl)-propyl]-1,8-naphthyridin-2(1H)-one, mp 137 to 138°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 6-methyl-2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 7-methyl-1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 165 to 166°C/AcOEt, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 6-methyl-2-(3-methylthiophenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 2), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 7-methyl-1-(3-methylthiophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 158 to 159°C/AcOEt, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 6-(pyridin-2-yl)-hexanoate (2.0 eq., prepared in Synthetic Example 11) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-2-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 163 to 165°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 6-(pyridin-3-yl)-hexanoate (2.0 eq., prepared in Synthetic Example 12) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-3-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 184.4 to 185.2°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eg.), methyl 6-(pyridin-4-yl)-hexanoate (2.0 eg., prepared in Synthetic Example 13) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-4-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 168.8 to 169.6°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • 2-(3-nitrophenylamino)nicotinaldehyde 1.0 eg.
  • methyl 6-(pyridin-4-yl)-hexanoate 2.0 eg., prepared in Synthetic Example 13
  • LDA 2.0 eq.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 7-(pyridin-3-yl)-heptanoate (2.0 eq., prepared in Synthetic Example 14) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[5-(3-pyridyl)pentyl]-1,8-naphthyridin-2(1H)-one, mp 155°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 7-(pyridin-4-yl)-heptanoate (2.0 eq., prepared in Synthetic Example 15) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[5-(pyridin-4-yl)pentyl]-1,8-naphthyridin-2(1H)-one, mp 188.8 to 189.6°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 9-(pyridin-4-yl)-nonanoate (1.5 eq., prepared in Synthetic Example 16) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[7-(pyridin-4-yl)heptyl]-1,8-naphthyridin-2(1H)-one, mp 189 to 192°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 4-(2-thienyl)-butanoate (1.5 eq., prepared in Synthetic Example 17) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(2-thienyl)ethyl)-1,8-naphthyridin-2(1H)-one, mp 175 to 176°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-furyl)-pentanoate (1.5 eq., prepared in Synthetic Example 18) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(2-furyl)propyl]-1,8-naphthyridin-2(1H)-one, mp 166 to 167°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(3-furyl)-pentanoate (1.5 eq., prepared in Synthetic Example 19) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(3-furyl)propyl]-1,8-naphthyridin-2(1H)-one, mp 185 to 186°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 6-(benzothiazol-2-yl)hexanoate (1.5 eq., prepared according to the procedure of Example 13 in JP, A, 8-208631 (1996)) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(benzothiazol-2-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 167.5 to 169.5°C/DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(pyridin-3-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 3), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(pyridin-3-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 178 to 180°C/DMF-EtOH.
  • 2-(pyridin-3-ylamino)nicotinaldehyde 1.0 eq., prepared in Synthetic Example 3
  • ethyl 5-(pyridin-4-yl)pentanoate 1.5 eq., prepared in Synthetic Example 10
  • LDA 1.5 eq.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-cyanophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(4-pyridyl)-pentanoate (1.2 eq., prepared in Synthetic Example 10) and LDA (1.2 eq.) to obtain 1-(3-cyanophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 202 to 203.5°C/DMF.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-methylsulfonylphenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 20), ethyl 5-(4-pyridyl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(3-methylsulfonylphenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 127 to 131°C/AcOEt, wherein the product was purified through flash column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-pyridyl)-pentanoate (1.5 eq., prepared in Synthetic Example 21) and LDA (1.5 eg.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 201 to 202°C/DMF, wherein the product was purified through flash column chromatography and recrystallization.
  • 2-(3-nitrophenylamino)nicotinaldehyde 1.0 eq.
  • ethyl 5-(2-pyridyl)-pentanoate 1.5 eq., prepared in Synthetic Example 21
  • LDA 1.5 eg.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 4-(2-benzothiazolyl)butanoate (1.5 eq., prepared in Synthetic Example 22) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[2-(benzothiazol-2-yl)ethyl]-1,8-naphthyridin-2(1H)-one, mp 178 to 179°C/DMF, wherein the product was purified through flash column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 5-(2-benzothiazolyl)pentanoate (1.5 eq., prepared in Synthetic Example 23) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(benzothiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 185 to 186°C/DMF, wherein the product was purified through flash column chromatography and recrystallization.
  • Example 1 The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-thiazolyl)-pentanoate (1.5 eq., prepared in Synthetic Example 24) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(thiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 198 to 199°C/DMF, wherein the product was purified through flash column chromatography and recrystallization.
  • a formula for one tablet (total amount per tablet: 150 mg) is given below: Compound of the present invention 20 mg Crystalline Cellulose 100 mg Corn Starch 28 mg Magnesium Stearate 2 mg
  • the ingredients were formulated into tablets by known methods according to general pharmaceutical rules prescribed in JPXIII.
  • a formula for one capsule (total amount per capsule: 180 mg) is given below: Compound of the present invention 50 mg Lactose 100 mg Corn Starch 28 mg Magnesium Stearate 2 mg
  • the ingredients were formulated into capsules by known methods according to general pharmaceutical rules prescribed in JPXIII.
  • the compound of the present invention (10 mg) was dissolved in 3 ml of physiological saline.
  • the solution was adjusted to pH 7 with 0.1 N aqueous sodium hydroxide, to which was added physiological saline to make the total volume 5 ml.
  • the resulting solution was dispensed to each ampule, and then subjected to heat sterilization to obtain injections.
  • the compound of the present invention (10 mg) was dissolved in a mixture of polyethylene glycol 300 (5.0 g), N-methyl-2-pyrrolidone (1.0 g) and Polysorbate 80 (1.0 g). The solution was passed through a 0.2 ⁇ m filter and dispensed to each ampule to obtain injections.
  • the ingredients were formulated into ointments by known methods according to general pharmaceutical rules prescribed in JPXIII.
  • the ingredients were blended to form a uniform mixture, spread in cloth, and shaped into patches (plasters).
  • the present invention relates to novel 1,8-naphthyridin-2(1H)-one derivatives.
  • the compounds of the present invention possess selective inhibition of PDE IV.
  • the compounds selectively inhibit PDE IV predominantly present in bronchial smooth muscle cells and inflammatory cells, thereby leading to an elevation of cAMP levels in such cells, with the result that it may be expected to achieve relaxation of bronchial smooth muscle and suppression of inflammatory cell activation.
  • the compounds are also less toxic as compared with the prior art PDE IV inhibitors.
  • the present invention provides pharmaceutical compositions comprising an effective amount of the said 1,8-naphthyridin-2(1H)-one derivative, and also drugs for preventing or treating diseases associated with PDE IV activity.
  • the present invention enables the production of safer anti-asthmatics which possess excellent pharmacological properties.

Claims (22)

  1. Verbindung der Formel (1):
    Figure 00810001
    worin:
    A eine unsubstituierte oder gegebenenfalls substituierte 5- oder 6gliedrige Heteroarylgruppe oder ein kondensierter Benzolring ist, bei dem eine der vorstehend definierten Heteroarylgruppen mit einem Benzolring kondensiert ist,
    B Kohlenstoff oder Stickstoff ist,
    R1 Wasserstoff, 1 bis 4 Kohlenstoffatome enthaltendes Alkyl, Trifluormethyl, Hydroxy, 1 bis 4 Kohlenstoffatome enthaltendes Alkoxy, ein von einer Carbonsäure abgeleiteter Rest, Amino oder eine einen Aminostickstoff enthaltende Gruppe ist,
    R2 Wasserstoff, Halogen, Cyan, Nitro, 1 bis 4 Kohlenstoffatome enthaltendes Alkylthio, 1 bis 4 Kohlenstoffatome enthaltendes Alkylsulfinyl, 1 bis 4 Kohlenstoffatome enthaltendes Alkylsulfonyl, Trifluormethyl, Hydroxy, 1 bis 4 Kohlenstoffatome enthaltendes Alkoxy, ein von einer Carbonsäure abgeleiteter Rest, Amino oder eine einen Aminostickstoff enthaltende Gruppe ist,
    m eine ganze Zahl sowohl von einschließlich 1 bis einschließlich 8 ist, oder ein pharmazeutisch annehmbares Salz davon.
  2. Verbindung gemäß Anspruch 1, wobei A eine 5- oder 6gliedrige Heteroarylgruppe ist und B Kohlenstoff ist, oder ein pharmazeutisch annehmbares Salz davon.
  3. Verbindung gemäß Anspruch 2, wobei A Pyridyl, 1-Oxypyridyl, Thienyl, Furyl oder Thiazolyl ist, oder ein pharmazeutisch annehmbares Salz davon.
  4. Verbindung gemäß Anspruch 2, wobei A Pyridyl oder 1-Oxypyridyl ist und m sowohl von einschließlich 1 bis einschließlich 5 ist, oder ein pharmazeutisch annehmbares Salz davon.
  5. Verbindung gemäß Anspruch 1, wobei A eine 5- oder 6gliedrige Heteroarylgruppe ist und B Stickstoff ist, oder ein pharmazeutisch annehmbares Salz davon.
  6. Verbindung gemäß Anspruch 5, wobei A Pyridyl, 1-Oxypyridyl, Thienyl, Furyl oder Thiazolyl ist, oder ein pharmazeutisch annehmbares Salz davon.
  7. Verbindung gemäß Anspruch 1, wobei A ein kondensierter Benzolring ist, bei dem eine der vorstehend definierten 5- oder 6gliedrigen Heteroarylgruppen an einen Benzolring kondensiert ist, und B Kohlenstoff ist, oder ein pharmazeutisch annehmbares Salz davon.
  8. Verbindung gemäß Anspruch 7, wobei A Benzothiazolyl ist, oder ein pharmazeutisch annehmbares Salz davon.
  9. Verbindung gemäß Anspruch 1, wobei A ein kondensierter Benzolring ist, bei dem eine vorstehend definierte 5- oder 6gliedrige Heteroarylgruppe an einen Benzolring kondensiert ist und B Stickstoff ist, oder ein pharmazeutisch annehmbares Salz davon.
  10. Verbindung gemäß Anspruch 9, wobei A Benzothiazolyl ist, oder ein pharmazeutisch annehmbares Salz davon.
  11. Verbindung gemäß einem der Ansprüche 1 bis 10, wobei R1 Wasserstoff oder 1 bis 4 Kohlenstoffatome enthaltendes Alkyl ist, oder ein pharmazeutisch annehmbares Salz davon.
  12. Verbindung gemäß einem der Ansprüche 1 bis 11, wobei R2 Wasserstoff, Halogen, Cyan, Nitro, 1 bis 4 Kohlenstoffatome enthaltendes Alkylthio, 1 bis 4 Kohlenstoffatome enthaltendes Alkylsulfinyl oder 1 bis 4 Kohlenstoffatome enthaltendes Alkylsulfonyl ist, oder ein pharmazeutisch annehmbares Satz davon.
  13. 1-(3-Nitrophenyl)-3-(pyridin-3-ylmethyl)-1,8-naphthyridin-2(1H)-on.
  14. 1-(3-Nitrophenyl)-3-[3-(pyridin-4-yl)propyl)-1,8-naphthyridin-2(1H)-on.
  15. 1-(3-Methylthiophenyl)-3-[3-(pyridin-4-yl)-propyl)-1,8-naphthyridin-2(1H)-on.
  16. 1-(Pyridin-3-yl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-on.
  17. Pharmazeutische Zusammensetzung, die eine wirksame Menge einer Verbindung gemäß einem der Ansprüche 1 bis 16 oder ein pharmazeutisch annehmbares Salz davon im Gemisch mit einem pharmazeutisch annehmbaren Träger umfaßt.
  18. Phosphodiesterase-IV-Inhibitor umfassend eine wirksame Menge einer Verbindung gemäß einem der Ansprüche 1 bis 16 oder ein pharmazeutisch annehmbares Salz davon.
  19. Antiasthmatikum umfassend eine wirksame Menge einer Verbindung gemäß einem der Ansprüche 1 bis 16 oder ein pharmazeutisch annehmbares Salz davon.
  20. Wirkstoff zur Prophylaxe und/oder Behandlung wenigstens einer mit einer Phosphodiesterase-IV-Aktivität zusammenhängenden, ausgewählten Krankheit oder abnormalen Bedingung, wobei der Wirkstoff eine wirksame Menge einer Verbindung gemäß einem der Ansprüche 1 bis 16 oder ein pharmazeutisch annehmbares Salz davon umfaßt.
  21. Wirkstoff, der eine wirksame Menge einer Verbindung gemäß einem der Ansprüche 1 bis 16 oder ein pharmazeutisch annehmbares Salz davon umfaßt, wobei der Wirkstoff zur Prophylaxe und/oder Behandlung wenigstens einer Erkrankung oder eines abnormalen Zustands dient, die aus der Gruppe ausgewählt sind, bestehend aus:
    (1) Bronchialasthma (einschließlich chronischem Bronchialasthma und atopischem Asthma), akuter Bronchitis, chronischer Bronchitis, asthmatischer Bronchitis, Lungenkrankheiten, Lungenemphysem, chronischer Lungenwegsverschlußkrankheit (COPD), akutem Atemnotsyndrom (ARDS) und anderen Atemwegserkrankungen;
    (2) atopischer Dermatitis, Konjunktivitis, Urtikaria, erworbenem Immunschwächesyndrom (AIDS), Keloidbildung, Rhinitis, Iridozyklitis, Gingivitis, Periodontitis, Dentoalveolitis, Gastritis, ulzerativer Colitis, Crohn-Krankheit, Magen-Darm-Ulkus, Ösophagitis, Myositis, Enzephalitis (einschließlich Myasthenia gravis, multipler Sklerose und Neuritis), Hepatitis, Narbengewebebildung, Nephritis (einschließlich proliferativer Nephritis), Peritonitis, Pleuritis, Skleritis, Sklerodermie, Verbrühungen oder Verbrennungen und anderen Entzündungskrankheiten;
    (3) Osteoarthritis, Gichtarthritis, rheumatoider Arthritis, malignem Rheumatismus, psoriatischer Arthritis und anderen systemischen oder lokalen Gelenkerkrankungen;
    (4) Reperfusionsverletzung, Transplantat-Wirt-Reaktion und anderen mit einer Organtransplantation verbundenen entzündlichen Zuständen;
    (5) Diabetes insipidus, Urethritis, Harninkontinenz, Zystitis, Reizblase, neurogener Blase, Urämie, Harnröhrenstörung, Pollakisurie, Ischurie und anderen mit der Miktion zusammenhängenden Erkrankungen;
    (6) Erkrankungen oder abnormalen Zuständen, die mit dem Tumornekrosefaktor (TNF) (zum Beispiel TNF-α usw.) und anderen Zytokinen (zum Beispiel IL-1, IL-4, IL-6 usw.) zusammenhängen, einschließlich Psoriasis, rheumatoider Arthritis, ulzerativer Kolitis, Crohn-Krankheit, Septikämie, septischem Schock, endotoxischem Schock, Sepsis durch einen gram-negativen Bacillus, Syndrom eines toxischen Schocks, Nephritis, Hepatitis, Infektion (Bakterien und Viren), Kreislaufversagen (Herzversagen, Arteriosklerose, Myokardinfarkt, zerebrale Apoplexie) und dergleichen;
    (7) malignen Tumoren, Leukämie, proliferativen Hautkrankheiten (Keratose und verschiedene Typen Dermatitiden), Bindegewebserkrankungen und anderen proliferativen Erkrankungen;
    (8) beeinträchtigtem Lernvermögen, Gedächtnis und Wahrnehmungsvermögen, das mit neurodegenerativen Störungen wie etwa Alzheimer-Krankheit und Parkinson-Krankheit, multipler Lateralsklerose, seniler Demenz, amyotropher Lateralsklerose, akuter demyelinierender Neuritis, Muskeldystrophie und anderen, mit einer Nervenfunktionsabnormalität verwandten Krankheiten in Beziehung steht;
    (9) manisch-depressiver Psychose, Schizophrenie, Angst, Panik und anderen Krankheiten, die mit einer Abnormalität mentaler Funktionen in Beziehung stehen;
    (10) Herzstillstand, Rückenmarksverletzung, Claudicatio intermittens, ischämischen Erkrankungen (Angina pectoris, Herzinfarkt, Hirnapoplexie, Kopfverletzung usw.) und einen Schutz von Nerven und Zellen erfordernden Krankheiten;
    (11) diabetischer Retinopathie, diabetischer Nephropathie, diabetischer Neurose, Amyloidose, Pankreatitis, Thyroiditis, Fettsucht, Prostatamegalie und anderer endokriner Krankheiten einschließlich Diabetes;
    (12) systemischem Lupus erythematosus (SLE), atrophischer Gastritis, Schilddrüsenkrankheiten, glomerulärer Nephritis, Orchitis, Nebennierenerkrankungen, hämolytischer Anämie, Oophoritis und anderen Autoimmunkrankheiten:
    (13) Bluthochdruck, Angina pectoris, Herzversagen, Myokarditis, externer Epikarditis, Endokarditis, Valvulitis und anderen kardiovaskulären Krankheiten;
    (14) Angiitis, Aneurysma, Endangiose, Thromboangiitis, Granulomatose, zerebrovaskulärer Angiitis, Arteriosklerose, Periangitis, Leukopänie, Thrombozytopänie, Boeck-Sarkoid und anderen Gefäß- und Blutsystemerkrankungen;
    (15) Kontaktdermatitis, Serumkrankheit, Wirkstoffallergie, Goodpasture-Syndrom, Lymphom, rheumatischem Fieber, AIDS, anaphylaktischem Schock und anderen mit Immunreaktionen oder allergischen Reaktion in Beziehung stehenden Krankheiten und
    (16) anderen Krankheiten, Störungen oder abnormalen Zuständen einschließlich Glaukom, spastischer Paralyse, Impotenz, Erkrankungen oder Unwohlsein, die von Schmerzen begleitet werden (Kontusion, Kopfschmerz usw.), Nacken-Schulter-Arm-Syndrom, Nephropathie, Niereninsuffizienz, Leberinsuffizienz, Fettleibigkeit usw.
  22. Wirkstoff gemäß Anspruch 20 oder 21 zur Prophylaxe und/oder Behandlung wenigstens einer Erkrankung oder abnormalen Zustands, ausgewählt aus der Gruppe bestehend aus:
    (1) Atemwegserkrankungen ausgewählt aus der Gruppe bestehend aus Bronchialasthma einschließlich chronischem Bronchialasthma und atopischem Asthma; akuter Bronchitis; chronischer Bronchitis; asthmatischer Bronchitis; Lungenkrankheiten; Lungenemphysem; chronischer Lungenwegsverschlußkrankheit (COPD) und akutem Atemnotsyndrom (ARDS) und
    (2) Entzündungskrankheiten, ausgewählt aus der Gruppe bestehend aus atopischer Dermatitis; Konjunktivitis; Urtikaria; erworbenem Immunschwächesyndrom (AIDS); Keloidbildung; Rhinitis; Iridozyklitis; Gingivitis; Periodontitis; Dentoalveolitis; Gastritis; ulzerativer Kolitis; Morbus Crohn; Magen-Darm-Ulkus; Ösophagitis; Myositis; Enzephalitis wie etwa Myasthenia gravis, multiple Sklerose und Neuritis; Hepatitis; Narbengewebebildung; Nephritis einschließlich proliferativer Nephritis; Peritonitis; Pleuritis; Skleritis; Sklerodermie und Verbrühungen oder Verbrennungen.
EP00979982A 1999-12-08 2000-12-07 Neue 1,8-naphtyridin-2(1h)-on-derivate Expired - Lifetime EP1236725B1 (de)

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BRPI0716604A2 (pt) * 2006-09-08 2013-04-09 Braincells Inc combinaÇÕes contendo um derivado de 4-acilaminopiridina
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